This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Bcl-2 family of proteins regulates apoptosis via protein-protein interactions among family members. We use structural and mutagenesis studies to understand the specificity of these interactions, specifically Mcl-1 with different BH3 peptides. Mcl-1/Bim BH3 complexes compared with other Bcl-2 protein/Bim complexes show structural differences, including different changes upon binding of the Bim BH3. Mutagenesis studies of the Bim BH3 sequence indicate many mutants, including mutations of conserved residues, can maintain binding to Mcl-1 and other Bcl-2 proteins. Structures of Mcl-1 in complex with some of these mutant Bim BH3 peptides reveal that flexibility of the BH3 peptide and the Mcl-1 protein allows for the accommodation of these mutations.